Randomised controlled trial of adjunctive inspiratory muscle training for patients with COPD.

BACKGROUND: This study aimed to investigate whether adjunctive inspiratory muscle training (IMT) can enhance the well-established benefits of pulmonary rehabilitation (PR) in patients with COPD. METHODS: 219 patients with COPD (FEV1: 42%±16% predicted) with inspiratory muscle weakness (PImax: 51±15 cm H2O) were randomised into an intervention group (IMT+PR; n=110) or a control group (Sham-IMT+PR; n=109) in this double-blind, multicentre randomised controlled trial between February 2012 and October 2016 (ClinicalTrials.gov NCT01397396). Improvement in 6 min walking distance (6MWD) was a priori defined as the primary outcome. Prespecified secondary outcomes included respiratory muscle function and endurance cycling time. FINDINGS: No significant differences between the intervention group (n=89) and the control group (n=85) in improvements in 6MWD were observed (0.3 m, 95% CI -13 to 14, p=0.967). Patients who completed assessments in the intervention group achieved larger gains in inspiratory muscle strength (effect size: 1.07, p<0.001) and endurance (effect size: 0.79, p<0.001) than patients in the control group. 75 s additional improvement in endurance cycling time (95% CI 1 to 149, p=0.048) and significant reductions in Borg dyspnoea score at isotime during the cycling test (95% CI -1.5 to -0.01, p=0.049) were observed in the intervention group. INTERPRETATION: Improvements in respiratory muscle function after adjunctive IMT did not translate into additional improvements in 6MWD (primary outcome). Additional gains in endurance time and reductions in symptoms of dyspnoea were observed during an endurance cycling test (secondary outcome) TRIAL REGISTRATION NUMBER: NCT01397396; Results.

The effects of signal transducer and activator of transcription three mutations on human platelets.

Involvement of signal transducer and activator of transcription 3 (STAT3) in inflammation is well known. Recently, a role for STAT3 in platelet activation and platelet production has been suggested. Platelets exhibit important immune functions and engagement of STAT3 in platelet physiology may link inflammation and hemostasis. This study investigated the effects of STAT3 loss-of-function mutations and single nucleotide polymorphisms (SNPs) in STAT3 on glycoprotein VI (GPVI)-mediated platelet activation and platelet numbers in humans. Two cohorts were studied. The first cohort concerned patients with STAT3 loss-of-function mutations. Platelet numbers were investigated in eight patients and GPVI-mediated platelet activation was functionally tested in four patients. Additional experiments were performed to investigate underlying mechanisms. The second cohort concerned 334 healthy volunteers and investigated the consequences of SNPs in STAT3 on GPVI-mediated platelet activation and platelet numbers. Platelet activation was lower in STAT3 loss-of-function patients at baseline and after stimulation of the GPVI receptor, reflected by decreased P-selectin expression. This was independent of gene transcription. Blockade of the adenosine di-phosphate (ADP) pathway resulted in a further decrease of P-selectin expression, particularly in STAT3 loss-of-function patients. In contrast, the SNPs in STAT3 did not influence GPVI-mediated platelet activation. Also, platelet numbers were not affected by STAT3 loss-of-function mutations, nor was there an association with the SNPs. In conclusion, STAT3 signaling does not seem to play a major role in thrombopoiesis. We confirm that STAT3 is involved in GPVI-mediated platelet activation in humans, independent of gene transcription. GPVI-mediated platelet activation is highly dependent on secondary ADP release. Our findings suggest that STAT3 modulation may affect inflammation, hemostasis, and their interaction.

Increased Platelet-Monocyte Interaction in Stable COPD in the Absence of Platelet Hyper-Reactivity.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is well known for its cardiovascular co-morbidities. Increased platelet-monocyte interaction is found in COPD and may reflect altered platelet function and a potential role for anti-platelet therapy. OBJECTIVES: The objectives were to investigate platelet-monocyte interaction, platelet activation and reactivity and plasmatic coagulation in stable COPD. METHODS: Platelet-monocyte interaction and platelet activation were determined by flow cytometry in 30 stable COPD patients and 25 controls. Platelet activation was measured by binding of fibrinogen to the activated fibrinogen receptor and platelet P-selectin expression at baseline and after platelet stimulation with platelet agonists. Plasmatic coagulation was measured by D-dimer and thrombin generation. RESULTS: Platelet-monocyte interaction was increased in stable COPD (median fluorescence intensity of platelet CD61 was 19.8 [IQR 14.0-33.2] vs. 10.0 [IQR 8.7-16.7], p = 0.002). In contrast, platelet activation and reactivity, reflected by fibrinogen binding and P-selectin expression, were the same in both groups. Plasma P-selectin and interleukin-6 were increased in COPD (p = 0.01 and p = 0.02, respectively), whereas soluble fibrinogen, D-dimer and thrombin generation were similar. CONCLUSIONS: Increased platelet-monocyte interaction was found in the absence of platelet hyper-reactivity and activation of plasmatic coagulation in stable COPD. Future clinical evaluation of the effects of different anti-platelet drugs in COPD is warranted, as anti-platelet therapy may interfere with platelet-monocyte interaction.

Integral Health Status-Based Cluster Analysis in Moderate-Severe COPD Patients Identifies Three Clinical Phenotypes: Relevant for Treatment As Usual and Pulmonary Rehabilitation.

PURPOSE: The purposes of the study are to identify clinical phenotypes that reflect the level of adaptation to the disease and to examine whether these clinical phenotypes respond differently to treatment as usual (TAU) and pulmonary rehabilitation (PR), the latter with its strong emphasis on improving adaptation. METHODS: Clusters were identified by a cluster analysis using data on many subdomains of the four domains of health status (HS) (physiological functioning, functional impairment, symptoms and quality of life) in 160 outpatients with chronic obstructive pulmonary disease (COPD) receiving TAU. By discriminant analysis in the TAU sample, all 459 PR patients could be assigned to one of the identified clusters. The effect of TAU and PR on HS was examined with paired t tests. RESULTS: Three distinct phenotypes were identified in the TAU sample. Two types were labelled adapted: phenotype 1 (moderate COPD-low impact on HS, n = 53) and phenotype 3 (severe COPD-moderate impact on HS, n = 73). One type was labelled non-adapted: phenotype 2 (moderate COPD-high impact on HS, n = 34). After 1-year TAU, the integral health status of all patients did not improve in any subdomain. In contrast, at the end of PR, significant improvements in HS were found in all three phenotypes especially the non-adapted. CONCLUSIONS: Different phenotypes exist in COPD that are based on behavioural aspects (i.e. the level of adaptation to the disease). Non-adapted patient responds better to treatments with a strong emphasis on improving adaptation by learning the patient better self-management skills. Knowing to which clinical phenotype a patient belongs helps to optimize patient-tailored treatment.

Consistency of medical record reporting of a set of indicators for proactive palliative care in patients with chronic obstructive pulmonary disease.

To identify patients hospitalized for an acute exacerbation of chronic obstructive pulmonary disease (COPD) who have a poor prognosis and might benefit from proactive palliative care, a set of indicators had been developed from the literature. A patient is considered eligible for proactive palliative care when meeting ≥2 criteria of the proposed set of 11 indicators. In order to develop a doctor-friendly and patient-convenient tool, our primary objective was to examine whether these indicators are documented consistently in the medical records. Besides, percentage of patients with a poor prognosis and prognostic value were explored. We conducted a retrospective medical record review of 33 patients. Five indicators; non-invasive ventilation (NIV), comorbidity, body mass index (BMI), previous admissions for acute exacerbation COPD and age were always documented. Three indicators; hypoxaemia and/or hypercapnia, professional home care and actual forced expiratory volume1% (FEV1%) were documented in more than half of the records, whereas the clinical COPD questionnaire (CCQ), medical research council dyspnoea (MRC dyspnoea) and the surprise question were never registered. Besides, 78.8% of the patients met ≥2 criteria and there was a significant association between meeting ≥2 criteria and mortality within 1 year (one-sided Fisher's exact test, p = 0.04). The set of indicators for proactive palliative care in patients with COPD appeared to be user-friendly and feasible.

Differences in systemic adaptive immunity contribute to the 'frequent exacerbator' COPD phenotype.

BACKGROUND: Some COPD patients are more susceptible to exacerbations than others. Mechanisms underlying these differences in susceptibility are not well understood. We hypothesized that altered cell mediated immune responses may underlie a propensity to suffer from frequent exacerbations in COPD. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from 24 stable COPD patients, eight frequent exacerbators (≥3 diary-card exacerbations/year) and 16 infrequent exacerbators (< 3 diary-card exacerbations/year). Detailed multi-parameter flow cytometry was used to study differences in innate and adaptive systemic immune function between frequent and infrequently exacerbating COPD patients. RESULTS: The 24 COPD patients had a mean (SD) age of 76.3 (9.4) years and FEV1 1.43 (0.60)L, 53.3 (18.3)% predicted. PBMCs of frequent exacerbators (FE) contained lower frequencies of CD4+ T central memory cells (CD4+ Tcm) compared to infrequent exacerbators (IE) (FE = 18.7 %; IE = 23.9 %; p = 0.035). This observation was also apparent in absolute numbers of CD4+ Tcm cells (FE = 0.17 × 10^6/mL; IE = 0.25 × 10^6/mL; p = 0.035). PBMCs of FE contained a lower frequency of CD8+ T effector memory cells expressing HLA-DR (Human Leukocyte Antigen - D Related) compared to IE COPD patients (FE = 22.7 %; IE = 31.5 %; p = 0.007). CONCLUSION: Differences in the adaptive systemic immune system might associate with exacerbation susceptibility in the 'frequent exacerbator' COPD phenotype. These differences include fewer CD4+ T central memory cells and CD8+ T effector memory cells. TRIAL REGISTRATION: Not applicable.

Revertant somatic mosaicism by mitotic recombination in dyskeratosis congenita.

Revertant mosaicism is an infrequently observed phenomenon caused by spontaneous correction of a pathogenic allele. We have observed such reversions caused by mitotic recombination of mutant TERC (telomerase RNA component) alleles in six patients from four families affected by dyskeratosis congenita (DC). DC is a multisystem disorder characterized by mucocutaneous abnormalities, dystrophic nails, bone-marrow failure, lung fibrosis, liver cirrhosis, and cancer. We identified a 4 nt deletion in TERC in a family with an autosomal-dominant form of DC. In two affected brothers without bone-marrow failure, sequence analysis revealed pronounced overrepresentation of the wild-type allele in blood cells, whereas no such skewing was observed in the other tissues tested. These observations suggest that this mosaic pattern might have resulted from somatic reversion of the mutated allele to the normal allele in blood-forming cells. SNP-microarray analysis on blood DNA from the two brothers indeed showed independent events of acquired segmental isodisomy of chromosome 3q, including TERC, indicating that the reversions must have resulted from mitotic recombination events. Subsequently, after developing a highly sensitive method of detecting mosaic homozygosity, we have found four additional cases with a mosaic-reversion pattern in blood cells; these four cases are part of a cohort of 17 individuals with germline TERC mutations. This shows that revertant mosaicism is a recurrent event in DC. This finding has important implications for improving diagnostic testing and understanding the variable phenotype of DC.

Prevention of exacerbations in patients with COPD and vitamin D deficiency through vitamin D supplementation (PRECOVID): a study protocol.

BACKGROUND: Vitamin D is well known for its function in calcium homeostasis and bone mineralisation, but is increasingly studied for its potential immunomodulatory properties. Vitamin D deficiency is a common problem in patients with COPD. Previous studies have not demonstrated a beneficial effect of vitamin D on exacerbation rate in COPD patients. However, subgroup analyses suggested protective effects in vitamin D deficient patients. Our objective is to assess the effect of vitamin D supplementation on exacerbation rate specifically in vitamin D deficient COPD patients. METHODS/DESIGN: We will perform a randomised, multi-center, double-blind, placebo-controlled intervention study. The study population consists of 240 COPD patients aged 40 years and older with vitamin D deficiency (25-hydroxyvitamin D concentration < 50 nmol/L). Participants will be recruited after an exacerbation and will be randomly allocated in a 1:1 ratio to receive vitamin D3 16800 IU or placebo orally once a week during 1 year. Participants will receive a diary card to register the incidence of exacerbations and changes in medication during the study period. Visits will be performed at baseline, at 6 months and at 12 months after randomisation. Participants will undergo spirometry, measurement of total lung capacity and assessment of maximal respiratory mouth pressure. Several physical performance and hand grip strength tests will be performed, questionnaires on quality of life and physical activity will be filled in, a nasal secretion sample and swab will be obtained and blood samples will be taken. The primary outcome will be exacerbation rate. DISCUSSION: This study will be the first RCT aimed at the effects of vitamin D supplementation on exacerbation rate in vitamin D deficient COPD patients. Also, in contrast to earlier studies that used infrequent dosing regimens, our trial will study effects of a weekly dose of vitamin D supplementation. Secondly, the immunomodulatory effects of vitamin D on host immune response of COPD patients and underlying mechanisms will be studied. Finally, the effects on physical functioning will be examined. TRIAL REGISTRATION: This trial is registered in ClinicalTrials.gov, ID number NCT02122627 . Date of Registration April 2014.

PROLONG: a cluster controlled trial to examine identification of patients with COPD with poor prognosis and implementation of proactive palliative care.

BACKGROUND: Proactive palliative care is not yet common practice for patients with COPD. Important barriers are the identification of patients with a poor prognosis and the organization of proactive palliative care dedicated to the COPD patient. Recently a set of indicators has been developed to identify those patients with COPD hospitalized for an acute exacerbation who are at risk for post-discharge mortality. Only after identification of these patients with poor prognosis a multi disciplinary approach to proactive palliative care with support of a specialized palliative care team can be initiated. METHODS/DESIGN: The PROLONG study is a prospective cluster controlled trial in which 6 hospitals will participate. Three hospitals are selected for the intervention condition based on the presence of a specialized palliative care team. The study population consists of patients with COPD and their main informal caregivers. Patients will be included during hospitalization for an acute exacerbation. All patients in the study receive standard care (usual care). Besides, patients in the intervention condition who meet two or more criteria of the set of indicators for proactive palliative care will have additionally regular consultations with a specialized palliative care team. The objectives of the PROLONG study are: 1) to assess the discriminating power of the proposed set of indicators (indicator study) and 2) to assess the effects of proactive palliative care for qualifying patients with COPD on the wellbeing of these patients and their informal caregivers (intervention study). The primary outcome measure of the indicator study is time to death for any cause. The primary outcome measure of the intervention study is the change in quality of life measured by the St George Respiratory Questionnaire (SGRQ) three months after inclusion. DISCUSSION: The PROLONG study may lead to better understanding of the conditions to start and the effectiveness of proactive palliative care for patients with COPD. Innovative aspects of the PROLONG study are the use of a set of indicators for proactive palliative care, the active involvement of a specialized palliative care team and the use of a patient-tailored proactive palliative care plan. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR4037.

Impact of switching to new spirometric reference equations on severity staging of airflow obstruction in COPD: a crosssectional observational study in primary care.

BACKGROUND: Severity of airflow obstruction in chronic obstructive pulmonary disease (COPD) is based on forced expiratory volume in one second expressed as percentage predicted (FEV1%predicted) derived from reference equations for spirometry results. AIMS: To establish how switching to new spirometric reference equations would affect severity staging of airflow obstruction in the Dutch primary care COPD patient population. METHODS: Spirometry tests of 3,370 adults aged >40 years with obstruction (postbronchodilator FEV1/forced vital capacity (FVC) <0.70) were analysed. The presence and severity of obstruction were defined using Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria. Postbronchodilator FEV1%predicted was calculated using three reference equations: corrected European Community of Steel and Coal (ECSC) (currently recommended in Dutch primary care), Swanney et al., and Global Lung Initiative (GLI). Discordances between severity classifications based on these equations were analysed. RESULTS: We studied 1,297 (38.5%) females and 2,073 males. Application of contemporary reference equations (i.e. Swanney and GLI) changed the GOLD severity stages obtained with the ECSC equations, mostly into milder stages. Severity of airflow obstruction was staged differently in 14.0% and 6.3%, respectively, when the Swanney et al. and GLI reference equations were applied. CONCLUSIONS: Compared with the (corrected) ECSC equations, switching to more contemporary reference equations would result in lower FEV1 predicted values and affect interpretation of spirometry by reclassifying 6-14% of primary care COPD patients into different (mostly milder) severity stages. If and how this will affect GPs' treatment choices in individual patients with COPD requires further investigation.

An autonomous mobile system for the management of COPD.

INTRODUCTION: Managing chronic disease through automated systems has the potential to both benefit the patient and reduce health-care costs. We have developed and evaluated a disease management system for patients with chronic obstructive pulmonary disease (COPD). Its aim is to predict and detect exacerbations and, through this, help patients self-manage their disease to prevent hospitalisation. MATERIALS: The carefully crafted intelligent system consists of a mobile device that is able to collect case-specific, subjective and objective, physiological data, and to alert the patient by a patient-specific interpretation of the data by means of probabilistic reasoning. Collected data are also sent to a central server for inspection by health-care professionals. METHODS: We evaluated the probabilistic model using cross-validation and ROC analyses on data from an earlier study and by an independent data set. Furthermore a pilot with actual COPD patients has been conducted to test technical feasibility and to obtain user feedback. RESULTS: Model evaluation results show that we can reliably detect exacerbations. Pilot study results suggest that an intervention based on this system could be successful.

Short-acting anticholinergic bronchodilation does not increase cardiovascular events in smokers with mild to moderate pulmonary obstruction.

BACKGROUND AND OBJECTIVE: We hypothesized that bronchodilation in patients with chronic obstructive pulmonary disease (COPD) increases the smoke-related risk to develop cardiovascular disease, and aimed to study the effect of short-acting anticholinergic bronchodilation and smoking on cardiovascular events. METHODS: We performed a secondary analysis on data from the Lung Health Study, a large randomized clinical trial of smokers with mild to moderate pulmonary obstruction, 35-60 years old, without cardiovascular comorbidity. We used Cox proportional survival analysis, controlling for several confounders, to study the effect on 5-year risk of fatal and/or non-fatal cardiovascular events. Secondary outcome encompassed fatal and non-fatal coronary events. RESULTS: Of 2745 participants, 23 (0.8%) died of cardiovascular disease. One hundred and sixty-two participants were hospitalized for a cardiovascular event, and 94 participants due to a coronary event. Survival analysis revealed no effect between smoking and short-acting anticholinergic bronchodilation on fatal and/or non-fatal cardiovascular events, hazard ratio = 1.12 (0.58-2.19), nor on coronary events, hazard ratio = 1.46 (0.60-3.56). CONCLUSIONS: Our study results show that short-acting anticholinergic bronchodilation had no detrimental effect on cardiovascular disease in smokers with mild to moderate pulmonary obstruction.

Decline of health status sub-domains by exacerbations of chronic obstructive pulmonary disease: a prospective survey.

BACKGROUND: Exacerbations of chronic obstructive pulmonary disease (COPD) are held responsible for a decline in health status (HS). This may not apply equally to all exacerbations, because different definitions are required for quite different illnesses. Selection of definitions and the sensitivity of the HS instrument may affect results regarding the impact of exacerbations. Sensitivity of a new HS instrument, which covers different and more aspects, has not yet been tested, with respect to exacerbations. OBJECTIVES: Confirmation of the negative HS effect of exacerbations by using a highly differentiated instrument, and to evaluate which aspects of HS are affected most. METHODS: One hundred and sixty-eight ambulatory patients with COPD were evaluated prospectively with regard to a wide range of HS aspects, at the beginning and end of a 1-year follow-up. Recording of symptom changes and treatment on monthly diary cards resulted in the identification of event-based exacerbations. HS was assessed via a newly validated instrument integrating both physiological and non-physiological sub-domains. Parametric correlations were calculated between exacerbation frequency and HS scores at the end of the study. Partial corre-lations were then explored using HS scores at baseline to correct for prior HS levels. RESULTS: Correlations between -exacerbation frequency and HS sub-domains were found to be frequent, predominantly in non-physiological sub--domains. After correction for hs scores at baseline, only 2 sub-domains (belonging to the main domain 'complaints') remained significantly but weakly correlated. CONCLUSION: Exacerbation frequency and HS show weak correlations after a year, but most of these disappear after correction for prior HS levels. In such exacerbations, aggravated HS probably takes much longer to manifest itself.

Manual vs. automated analysis of polysomnographic recordings in patients with chronic obstructive pulmonary disease.

PURPOSE: The sleep quality, as assessed by polysomnography (PSG), of patients with chronic obstructive pulmonary disease (COPD) can be severely disturbed. The manual analysis of PSGs is time-consuming, and computer systems have been developed to automatically analyze PSGs. Studies on the reliability of automated analyses in healthy subjects show varying results, and the purpose of this study was to assess whether automated analysis of PSG by one certain automatic system in patients with COPD provide accurate outcomes when compared to manual analysis. METHODS: In a retrospective study, the full-night polysomnographic recordings of patients with and without COPD were analyzed automatically by Matrix Sleep Analysis software and manually. The outcomes of manual and automated analyses in both groups were compared using Bland-Altman plots and Students' paired t tests. RESULTS: Fifty PSGs from patients with COPD and 57 PSGs from patients without COPD were included. In both study groups, agreement between manual and automated analysis was poor in nearly all sleep and respiratory parameters, like total sleep time, sleep efficiency, sleep latency, amount of rapid eye movement sleep and other sleep stages, number of arousals, apnea-hypopnea index, and desaturation index. CONCLUSION: Automated analysis of PSGs by the studied automated system in patients with COPD has poor agreement with manual analysis when looking at sleep and respiratory parameters and should, therefore, not replace the manual analysis of PSG recordings in patients with COPD.

Bronchodilation and smoking interaction in COPD: a cohort pilot study to assess cardiovascular risk.

BACKGROUND: Smoking and bronchodilator treatment are both extensively studied as key elements in patients with chronic obstructive pulmonary disease. However, little is known about whether or not these elements interact in terms of developing cardiovascular diseases in patients with COPD. OBJECTIVES: To explore to what extent the risk of developing ischemic cardiovascular disease in COPD patients is mediated by smoking status, use of bronchodilators and--specifically--their interaction. METHODS: We performed an observational pilot study on a relatively healthy Dutch COPD cohort from a primary care diagnostic center database with full information on spirometry tests, smoking status, bronchodilator use and other prescribed medication. We defined first ischemic cardiovascular events as primary outcome, measured by first prescription of antiplatelet drugs and/or nitrates. Unadjusted analyses by Kaplan-Meier were followed by adjusted Cox' proportional hazards. RESULTS: 845 COPD patients, totaling 2,169 observation years, were included in the analyses. We observed an increased risk for nonfatal ischemic cardiovascular events by smoking (adjusted HR=3.58, p=0.001) and a protective effect of bronchodilators (adjusted HR=0.43, p=0.01). Although the protective effect of bronchodilators appears to be substantially minimized in patients that persist in smoking, we could not statistically confirm a hazardous interaction between bronchodilators and smoking (HR 2.50, p=0.21). CONCLUSION: Our study reveals bronchodilators may protect from ischemic cardiovascular events in a relatively 'healthy' COPD population. We did not confirm a hazardous interaction between bronchodilators and smoking, although we observed current smokers benefit substantially less from the protective effect of bronchodilators.

Lung function decline in relation to diagnostic criteria for airflow obstruction in respiratory symptomatic subjects.

BACKGROUND: Current COPD guidelines advocate a fixed < 0.70 FEV1/FVC cutpoint to define airflow obstruction. We compared rate of lung function decline in respiratory symptomatic 40+ subjects who were 'obstructive' or 'non-obstructive' according to the fixed and/or age and gender specific lower limit of normal (LLN) FEV1/FVC cutpoints. METHODS: We studied 3,324 respiratory symptomatic subjects referred to primary care diagnostic centres for spirometry. The cohort was subdivided into four categories based on presence or absence of obstruction according to the fixed and LLN FEV1/FVC cutpoints. Postbronchodilator FEV1 decline served as primary outcome to compare subjects between the respective categories. RESULTS: 918 subjects were obstructive according to the fixed FEV1/FVC cutpoint; 389 (42%) of them were non-obstructive according to the LLN cutpoint. In smokers, postbronchodilator FEV1 decline was 21 (SE 3) ml/year in those non-obstructive according to both cutpoints, 21 (7) ml/year in those obstructive according to the fixed but not according to the LLN cutpoint, and 50 (5) ml/year in those obstructive according to both cutpoints (p = 0.004). CONCLUSION: This study showed that respiratory symptomatic 40+ smokers and non-smokers who show FEV1/FVC values below the fixed 0.70 cutpoint but above their age/gender specific LLN value did not show accelerated FEV1 decline, in contrast with those showing FEV1/FVC values below their LLN cutpoint.

Exercises commonly used in rehabilitation of patients with chronic obstructive pulmonary disease: cardiopulmonary responses and effect over time.

OBJECTIVES: To compare conventional exercise-based assessment of pulmonary rehabilitation (PR) with improvement in training exercises employed during a PR program, and to describe the cardiopulmonary response of different training exercises during PR of patients with chronic obstructive pulmonary disease (COPD). DESIGN: Observational study. SETTING: Inpatient PR. PARTICIPANTS: Patients with moderate to very severe COPD (N=18). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Cardiopulmonary responses to interval cycling, arm exercise, and a test of functional activities of daily living (ADLs) were evaluated during the PR training program using a mobile telemetric breath-by-breath system. The effects of PR were evaluated by comparing pre-PR and post-PR training activities, incremental and constant work-rate cycling, and a 6-minute walk test. RESULTS: Interval cycling and the ADLs test were moderate-intensity to heavy-intensity exercises (70%-80% of maximal oxygen consumption), while the arm exercise was a low-intensity activity (40% of maximal oxygen consumption). After 12 weeks of PR, cycle load, arm weights, and walking distances during training activities had increased alongside increased muscle mass. At iso-intensities, no cardiopulmonary changes in the training exercises were observed. Exercise duration of constant work-rate cycling and 6-minute walk distance increased by 160% and 14%, respectively, after PR, with concurrent right-shifts of anaerobic threshold and a decrease in heart rate. CONCLUSIONS: Supervised increases in weight, load, and walking distance during training activities were useful clinical outcomes for patients, demonstrating the beneficial effects of progressive training on physical performance. However, for physiologic evaluation of PR, conventional tests, such as maximal incremental cycling, endurance cycling, and a 6-minute walk test, had greater validity. Physiologic evaluation of the training exercises showed that the training program complied with the training recommendations for PR.

Pursed-lips breathing improves inspiratory capacity in chronic obstructive pulmonary disease.

BACKGROUND: In patients with severe chronic obstructive pulmonary disease (COPD), pursed-lips breathing (PLB) improves the pulmonary gas exchange and hyperinflation measured by electro-optic coupling. The response to PLB in inspiratory lung function tests is not known. OBJECTIVES: The purpose of this study was to measure the effect of PLB on inspiratory parameters. METHODS: Thirty-five subjects with stable COPD and a forced expiratory volume in first second (FEV(1)) <50% of the predicted value were tested for the following primary parameters before and immediately after PLB, and 5 min later: forced inspiratory vital capacity, inspiratory capacity (IC), forced inspiratory volume in first second, maximal inspiratory flow at 50% of vital capacity, and peak inspiratory flow. Patients were also tested for the following secondary parameters: vital capacity, FEV(1), breathing frequency, end-tidal CO(2) tension, and oxygen saturation. RESULTS: Of all the primary parameters only IC (p = 0.006) improved significantly; with regard to the secondary parameters, the mean oxygen saturation was improved by 1% (p = 0.005) and the mean end-tidal CO(2) tension and breathing frequency decreased significantly (p < 0.0001 for both) to 3.2 mm Hg and 3.1 breaths/min, respectively. After 5 min the effects diminished. CONCLUSION: Improved IC after PLB indicates less hyperinflation in patients with severe COPD; there was no effect on parameters of flow.

Health status in COPD cannot be measured by the St George's Respiratory Questionnaire alone: an evaluation of the underlying concepts of this questionnaire.

BACKGROUND: Improving patients' health status is one of the major goals in COPD treatment. Questionnaires could facilitate the guidance of patient-tailored disease management by exploring which aspects of health status are problematic, and which aspects are not. Health status consists of four main domains (physiological functioning, symptoms, functional impairment, and quality of life), and at least sixteen sub-domains. A prerequisite for patient-tailored treatment is a detailed assessment of all these sub-domains. Most questionnaires developed to measure health status consist of one or a few subscales and measure merely some aspects of health status. The question then rises which aspects of health status are measured by these instruments, and which aspects are not covered. As it is one of the most frequently used questionnaires in COPD, we evaluated which aspects of health status are measured and which aspects are not measured by the St George's Respiratory Questionnaire (SGRQ). METHODS: One hundred and forty-six outpatients with COPD participated. Correlations were calculated between the three sections of the SGRQ and ten sub-domains of the Nijmegen Integral Assessment Framework, covering Symptoms, Functional Impairment, and Quality of Life. As the SGRQ was not expected to measure physiological functioning, we did not include this main domain in the statistical analyses. Pearson's r > or = 0.70 was used as criterion for conceptual similarity. RESULTS: The SGRQ sections Symptoms and Total showed conceptual similarity with the sub-domain Subjective Symptoms (main domain Symptoms). The sections Activity, Impacts and Total were conceptual similar to Subjective Impairment (main domain Functional Impairment). The SGRQ sections were not conceptual similar to other sub-domains of Symptoms, Functional Impairment, nor to any sub-domain of Quality of Life. CONCLUSIONS: The SGRQ could facilitate the guidance of disease management in COPD only partially. The SGRQ is appropriately only for measuring problems in the sub-domains Subjective Symptoms and Subjective Impairment, and not for measuring problems in other sub-domains of health status, such as Quality of Life.

Pneumonitis as a consequence of (peg)interferon-ribavirin combination therapy for hepatitis C: a review of the literature.

Combination of peginterferon and ribavirin is the current therapy for chronic hepatitis C infection (HCV). Interstitial pneumonitis is a rare side-effect of HCV therapy and is an important cause of dose reduction or discontinuation, impairing success of antiviral therapy. We performed a review of the literature in order to present diagnostic modalities and possible treatments for pneumonitis and to offer guidelines. We searched for cases where pneumonitis as a side-effect of HCV treatment was documented. First we performed a literature search via PubMed and Web of Science interface and second we searched three drug toxicity databases. We systematically analyzed all case reports with respect to clinical manifestations, type of treatment, and outcome. A literature search revealed 19 articles, containing 25 case descriptions, while we traced 33 cases from the drug toxicity databases. Pneumonitis presented with any of the combination of fever, dyspnea, and cough and can arise with any type of (conventional or pegylated) interferon. Mortality secondary to pneumonitis was seen in 7% of cases, exclusively with peginterferon alpha-2b. In most cases therapy was discontinued and steroids were started. Interferon-induced pneumonitis during HCV treatment is a severe complication and should be recognized in order to prevent further pulmonary damage and/or death.